Search

Purpose: Microinvasive glaucoma surgery (MIGS) has become an important treatment approach for primary open-angle glaucoma, although the safe and long-term effective lowering of intraocular pressure with currently available implants for MIGS is not yet achieved to a satisfactory extent. The study focusses on the development and in vitro and in vivo testing of a novel microstent for MIGS., Methods: A silicone elastomer-based microstent was developed. Implants were manufactured using dip coating, fs-laser cutting, and spray coating. Within the current study no antifibrotic drug was loaded into the device. Sterilized microstents were analyzed in vitro regarding pressure-flow characteristics and biocompatibility. Six New Zealand white rabbits were implanted with a microstent draining the aqueous humor from the anterior chamber into the subconjunctival space. Drainage efficacy was evaluated using oculopressure tonometry as a transient glaucoma model. Noninvasive imaging was performed., Results: Microstents were manufactured successfully and characterized in vitro. Implantation in vivo was successful for four animals with additional device fixation. Without additional fixation, dislocation of microstents was found in two animals. Safe and effective intraocular pressure reduction was observed for the four eyes with correctly implanted microstent during the 6-month trial period., Conclusions: The described microstent represents an innovative treatment approach for MIGS. The incorporation of a selectively antifibrotic drug into the microstent drug-elutable coating will be addressed in future investigations., Translational Relevance: The current preclinical study successfully provided proof of concept for our microstent for MIGS which is suitable for safe and effective intraocular pressure reduction and offers promising perspectives for the clinical management of glaucoma.

In this paper, approaches for the realization of high-resolution periodic structures with gap sizes at sub-100 nm scale by two-photon polymerization (2PP) are presented. The impact of laser intensity on the feature sizes and surface quality is investigated. The influence of different photosensitive materials on the structure formation is compared. Based on the elliptical geometry character of the voxel, the authors present an idea to realize high-resolution structures with feature sizes less than 100 nm by controlling the laser focus position with respect to the glass substrate. This investigation covers structures fabricated respectively in the plane along and perpendicular to the major axis of voxel. The authors also provide a useful approach to manage the fabrication of proposed periodic structure with a periodic distance of 200 nm and a gap size of 65 nm.

Glaucoma drainage devices are used in surgical glaucoma therapy. Success of controlling the intraocular pressure is limited due to fibrous implant encapsulation and fibrin coating on the implant which lead to drainage obstructions. An innovative implant with a magnetically adjustable valve was developed. The valve opening of the implant should eliminate inflammatory products from the outflow area and affect fibrous tissue formation to achieve a sufficient long-term aqueous humour outflow. Lifting of this valve should disturb cell adhesion by exerting mechanical forces. Before testing this hypothesis, the flow characteristics of glaucoma drainage devices, especially the outflow resistance by regular IOP, should be considered in a pilot study, as they are important in preventing too low postoperative intraocular pressure known as ocular hypotony. Therefore, two prototypes of the innovative implant differing in their valve area design were examined regarding their flow characteristics in a limited animal experiment lasting two weeks. Ten healthy New Zealand White rabbits were divided into two groups (A & B) with different implanted prototypes. Daily, tonometry and direct ophthalmoscopy were performed to assess the intraocular pressure and the inflammatory reaction of the eye. After two weeks, the rabbits were euthanised to evaluate the initially histological inflammatory reaction to the implant. In group A, one case of hypotony emerged. When considering the entire observation period, a highly statistically significant difference between the intraocular pressure in the operated eye and that in the control eye was detected in group A (p < 0.0001) in contrast to group B (p = 0.0063). The postoperative inflammatory signs decreased within two weeks. Histologically, a typical but low level foreign body reaction with macrophages and lymphocytes as well as mild to moderate fibrosis was seen after the short experimental period. Based on our tonometric results, prototype B seems to be the system of choice for further research assessing its long-term function and biocompatibility., Competing Interests: Two authors (HL, SN) belong to commercial companies (ROWIAK GmbH, Augenärzte am Aegi), respectively. Their Author Contributions are available. ROWIAK GmbH disposed a patent (US20180250166A1) and HL is marked as inventor. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.

Purpose:  The purpose of this study is to analyze the static magnetic field interactions for an ophthalmic-magnetic shunt implant with a ferromagnetic steel plate in a thin silicon layer. The plate is used for opening of a valve flap. Ten different sizes of this steel plate were investigated to characterize the relationship between the size of the metal and the magnetic forces of the static magnetic field of a 3.0 T MRI., Materials and Methods:  The magnetic translation force F z was quantified by determining the deflection angle using the deflection angle test (ASTM F 2052). The torque was qualitatively estimated by using a 5-point grading scale (0: no torque; + 4: very strong torque) according to Sommer et al. 11. For the visual investigation of the function of the metal plate both prototypes were positioned at the magnetic field's spatial gradient and at the magnet's isocenter. The stitches were exposed to the thousandfold of the translational force by a dynamometer., Results:  The translational force was found to be 10 times greater than the weight of a single plate. The plates were exposed to a high torque (grade 3 to 4). The seams and the tissue withstood more than a thousandfold of the determined translational force. No spontaneous, uncontrolled opening of the valve flap was visible in the MRI, as a result of which the intraocular pressure could decrease considerably., Conclusion:  Due to the small size of the plates the translational force and the torque will be compensated by the silicon layer and also by the fixation in the eye., Key Points:   · Magnetic forces will be compensated by silicon layer and fixation in the eye.. · The magnetic-ophthalmological implant is not restricted in its function by the MRI magnetic field.. · The ophthalmic magnetic shunt implant can be considered conditionally MRI-safe.., Citation Format: · Bodenstein A, Lüpke M, Seiler C et al. Evaluation of the static magnetic field interactions for a newly developed magnetic ophthalmic implant at 3 Tesla MRI. Fortschr Röntgenstr 2019; 191: 209 - 215., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Silicones are widely used in medical applications. In ophthalmology, glaucoma drainage devices are utilized if conservative therapies are not applicable or have failed. Long-term success of these devices is limited by failure to control intraocular pressure due to fibrous encapsulation. Therefore, different medical approved silicones were tested in vitro for cell adhesion, cell proliferation and viability of human Sclera (hSF) and human Tenon fibroblasts (hTF). The silicones were analysed also depending on the sample preparation according to the manufacturer's instructions. The surface quality was characterized with environmental scanning electron microscope (ESEM) and water contact angle measurements. All silicones showed homogeneous smooth and hydrophobic surfaces. Cell adhesion was significantly reduced on all silicones compared to the negative control. Proliferation index and cell viability were not influenced much. For development of a new glaucoma drainage device, the silicones Silbione LSR 4330 and Silbione LSR 4350, in this study, with low cell counts for hTF and low proliferation indices for hSF, and silicone Silastic MDX4-4210, with low cell counts for hSF and low proliferation indices for hTF, have shown the best results in vitro. Due to the high cell adhesion shown on Silicone LSR 40, 40,026, this material is unsuitable., Competing Interests: The authors declare no conflict of interest. Our financial sponsors had no role in the design of the study neither in the collection, analyses, or interpretation of data nor in the writing of the manuscript and the decision to publish the results.

Within this paper we analyzed the technical feasibility of a novel microstent for glaucoma therapy. For lowering of intraocular pressure, the flexible polyurethane (PUR) implant is designed to drain aqueous humour from the anterior chamber of the eye into subconjunctival, or alternatively suprachoroidal, space. The microstent includes a biodegradable, flow resisting polymer membrane serving as temporary flow resistance for the prevention of early postoperative hypotony. A biodegradable local drug delivery (LDD)-device was designed to prevent fibrous encapsulation. Biodegradable components were made of flexible, nonwoven membranes of Poly(4-hydroxybutyrate) (P(4HB)). Polymer samples and microstent prototypes were manufactured by means of dip coating, electrospinning and femtosecond-laser micromachining and characterized in vitro with regard to structural and fluid mechanical properties, degradation behavior and drug release. Bending stiffness of PUR-tubing (62.53 ± 7.57 mN mm 2 ) is comparable to conventional glaucoma drainage devices in a tube-plate design. Microstent prototypes yield a flow resistance of 2.4 ± 0.6 mmHg/μl min -1 which is close to the aspired value corresponding to physiological pressure (15 mmHg) and aqueous humour flow (2 μl min -1 ) conditions inside the eye. Degradation of electrospun P(4HB) specimens was found to be almost completely finished after six months in vitro. Within this time frame, flow capacity of the microstent increases, which is beneficial to compensate potentially increasing flow resistance of fibrous tissue in vivo. Fast drug release of the LDD-device was found. One microstent prototype was implanted into a porcine eye ex vivo. Future preclinical studies will allow further information about Microstent performance.

ISO 10993-5 provides one of the accepted standards for testing the biotoxicity of new materials. All of the recommended test procedures rely upon the uptake or metabolism of dye by living cells. Results of direct contact tests can be potentially compromised by interaction or adsorption of the dye or its metabolic products. Therefore, the aim of the current study was to validate the use of the eGFP signal of transfected NIH-3T3 fibroblasts with the results of the MTT test in order to provide a test procedure that is very close to the ISO 10993-5 but has the advantage of not relying on the addition of dye. Our tests show that the MTT assay detects cytotoxicity in the eGFP NIH-3T3 cells at least as well as in the L929 cells. To facilitate the validation, we chose to integrate the fluorescence measurements into the MTT test procedure. To that end, an additional washing step was introduced. Additionally, medium without phenol red was used, resulting in a very high correlation of both measurements. Without these modifications, the fluorescence test was comparable to the MTT test in its ability to detect the cytotoxic potential of substances; however, it did result in slightly elevated IC50 concentrations. As the results of both tests correlated highly, measurement of the eGFP signal appears to present a reliable tool for detecting cytotoxicity of materials in line with the ISO 10993-5 norm with the advantage of avoiding the addition of dyes and the subsequent potential interaction with test materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 715-722, 2017., (© 2015 Wiley Periodicals, Inc.)

Background: Additive manufacturing and 3D printing create new paths for the design and manufacturing of implants. Technologies with high resolution are required for the development of microstructured eye implants. In the present study, we demonstrate how these technologies can be used during the design development and manufacturing of a multifocal diffractive aspheric intraocular lens., Material and Methods: Multiphoton polymerisation (MPP) is used to manufacture a diffractive relief with resolution in the sub-micrometer range. The relief is applied to the moulded body of a refractive lens, forming a trifocal lens. Propagation of light behind the lens is visualised in water with fluorescein., Results: Multifocal lenses were successfully manufactured with this approach. The optical design with three foci is confirmed by the light propagation images. The images even clearly demonstrate the impact of the refractive and diffractive elements and may provide information on artefacts and aberrations., Conclusions: Multiphoton polymerisation is an interesting tool for the flexible manufacturing of complex multifocal lenses. With future technological progress in 3D printing with MPP, this is a promising method for on-demand manufacturing of patient individual intraocular lenses., (Georg Thieme Verlag KG Stuttgart · New York.)

The utilisation of the diffractive properties of Fresnel zone plates offers the possibility of intraocular lens designs with multiple foci. Such intraocular lenses can be manufactured by two-photon polymerisation (2PP). This paper explains the underlying concept and shows the principles for visualisation of the focus properties of such implants., (Georg Thieme Verlag KG Stuttgart · New York.)

The two-photon polymerization technique (2PP) uses non-linear absorption of femtosecond laser pulses to selectively polymerize photosensitive materials. 2PP has the ability to fabricate structures with a resolution from tens of micrometers down to hundreds of nanometers. Three-dimensional microstructuring by the 2PP technique provides many interesting possibilities for biomedical applications. This microstructuring technique is suitable with many biocompatible polymeric materials, such as polyethylene glycol, polylactic acid, polycaprolactone, gelatin, zirconium-based hybrids, and others. The process of fabrication does not require clean room conditions and does not use hazard chemicals or high temperatures. The most beneficial property of 2PP is that it is capable of producing especially complex three-dimensional (3-D) structures, including devices with overhangs, without using any supportive structure. The flexibility in controlling geometries and feature sizes and the possibility to fabricate structures without the addition of new material layers makes this technique particularly appealing for fabrication of 3-D scaffolds for tissue engineering.

This paper describes methods for design, manufacturing and characterization of a micro-mechanical valve for a novel glaucoma implant. The implant is designed to drain aqueous humour from the anterior chamber of the eye into the suprachoroidal space in case of an elevated intraocular pressure (IOP). In contrast to any existing glaucoma drainage device (GDD), the valve mechanism is located in the anterior chamber and there, surrounded by aqueous humour, immune to fibrosis induced failure. For the prevention of hypotony the micro-mechanical valve is designed to open if the physiological pressure difference between the anterior chamber and the suprachoroidal space in the range of 0.8 mmHg to 3.7 mmHg is exceeded. In particular the work includes: (i) manufacturing and morphological characterization of polymer tubing, (ii) mechanical material testing as basis for (iii) the design of micro-mechanical valves using finite element analysis (FEA), (iv) manufacturing of microstent prototypes including micro-mechanical valves by femtosecond laser micromachining and (v) the experimental fluid-mechanical characterization of the manufactured microstent prototypes with regard to valve opening pressure. The considered materials polyurethane (PUR) and silicone (SIL) exhibit low elastic modulus and high extensibility. The unique valve design enables a low opening pressure of micro-mechanical valves. An ideal valve design for PUR and SIL with an experimentally determined opening pressure of 2 mmHg and 3.7 mmHg is identified. The presented valve approach is suitable for the inhibition of hypotony as a major limitation of today's GDD and will potentially improve the minimally invasive treatment of glaucoma.

A pressure-controlled microstent could permanently normalise the intraocular pressure (IOP) for open-angle glaucoma therapy by drainage into the suprachoroidal space. The complex requirements demand new technical solutions as well as an improved understanding of specific cell biological processes at the implant's surface to develop effective local drug delivery (LDD) concepts and surface modifications. Fluid mechanical requirements were derived from physiological data and the analysis of commercial glaucoma implants. The technological basics for the production of suitable structures are refined ultra-short pulse laser technology and 2-photon polymerisation (2PP). All known glaucoma implants induce unwanted cell proliferation resulting in a loss of function. It is assumed that the activity of fibroblasts is low in the suprachoroidal space. However, it was seen that LDD concepts are required to control cell proliferation. Fibroblasts from sclera and choroidea were isolated und cultured as the most relevant cell types for in vitro investigation. Potential materials and drugs were investigated by cell viability tests for biocompatibility or suppression of cell viability. The fluid mechanical analysis leads to smallest stent lumina (ID = 50 µm) at anatomically suitable implant lengths (7 - 10 mm). Only pressure control can manage the individual conditions with changing IOP. Finite element analysis of valves showed the need for highly flexible structures. This can be achieved by combining basic structures with micromechanically active valves added by 2PP. The potential materials show perfect in vitro and in vivo biocompatibility. Ormocers which are best suited for 2PP are also highly biocompatible. The selected drugs paclitaxel and triamcinolon acetonide open a wide therapeutic window to impair fibroblast growth. The surgical procedure was established by implantation of prototypes in rabbit eyes, connecting the anterior chamber with the suprachoroidal space. Highly flexible implants are required for correct placement within the eye. The new concept of the microstent combines biomechanical approaches, technologies for microfabrication and current LDD concepts and opens new perspectives for glaucoma therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Multi-focus two-photon polymerization with a spatial light modulator is demonstrated. The spatial light modulator generates multi-focus spots via phase modulation technique controlled by a computer generated hologram (CGH) pattern. Each focus spot can be individually addressed in position and laser intensity. The multi-focus two-photon polymerization technique allows the fabrication of complex 2-D and 3-D structures both symmetric and asymmetric. Smooth sine curved polymerized lines with amplitude of 5 microm and a period of 200 microm were obtained by fast switching of the CGH patterns.

The temporal characteristics of ultrashort hard-x-ray pulses generated in a femtosecond-laser-driven x-ray diode are investigated for what is believed to be the first time. Copper Kalpha x-ray pulses with a duration of a few picoseconds are measured with a jitter-free x-ray streak camera.

Resonant spectral structures of four-wave mixing (FWM) in molecular sodium are investigated. For a double- ? configuration with strong-weak-strong-weak fields, split components in FWM spectra induced by the strong pump fields are observed. It is shown that the split components merge into a single peak for a certain ratio of the strong field intensities. A correlation between the level-splitting effects and the saturation behavior of the FWM signal is experimentally demonstrated.

Efficient continuous resonant frequency mixing omega(4) = omega(1) - omega(2) + omega(3) in Na(2) has been realized. A bichromatic field (lambda(1) = 488 nm, lambda(2) = 525 nm), generated by an Ar(+)-laser-pumped Na(2) Raman laser, and radiation at lambda(3) = 655 nm from a dye laser interact resonantly with corresponding transitions X(1)Sigma(g)(+)(upsilon = 3, J = 43) ? B(1)Pi(u)(6, 43) ? X(1)Sigma(g)(+)(13, 43) ? A(1)Sigma(g)(+)(24, 44) in a test Na(2) heat pipe. For input powers of 200, 25, and 400 mW an output beam of as much as 0.2 mW at lambda(4) = 599 nm has been observed. Measured parameter dependences indicate an influence of interference effects. This is directly related to the discussion of lasing without inversion.